This project studies gene therapy for chronic granulomatous diseases (CGD) and other inherited immune diseases affecting human phagocytes, and also studies use of gene therapy to augment phagocyte host defense against chronic intracellular infections such as tuberculosis and other mycobacterial infections. CGD are a group of 4 distinct genetic disorders with common phenotype characterized by life-threatening recurrent infections caused by failure of blood neutrophils and monocytes to produce superoxide and hydrogen peroxide. CGD results from the failure to produce any of the components of the NADPH oxidase. During the past year we have conducted a Phase I clinical trial of gene therapy for the p47phox deficient autosomal recessive form of CGD. Five adult patients with CGD were treated with G-CSF to mobilize to the peripheral blood CD34+ hematopoietic myeloid progenitor cells, which were harvested and transduced with retrovirus to transfer the corrective gene into these cells. The cells were returned to the patients' blood following gene transfer in culture. The patients were not given any treatments to enhance engraftment. By three weeks following intravenous administration of these autologous gene corrected blood progenitor cells small numbers of functionally corrected oxidase positive neutrophils were detected in all five patients. Over the next week to 10 days the number of oxidase positive neutrophils in the peripheral blood rose to a peak frequency ranging from 1 in 1500 to 1 in 30,000 neutrophils in different patients and then decreased over several months to undetectable levels. While this frequency was very low and the correction not permanent, the level of oxidant production in these small numbers of corrected cells was not distinguishable from that of normal. The procedures were not associated with any adverse reactions in the patients. In related studies of a mouse model of p47phox deficient CGD gene therapy was performed using retrovirus vector targeting bone marrow. A long term correction of 2% of circulating neutrophils was achieved in mice conditioned by moderate doses of radiation ( an approach to conditioning that might be clinically useful). Following an intraperitoneal challange with bacteria the mice treated with gene therapy had signficantly increased survival compared to control CGD mice. Taken together, the preliminary results of our human trial of gene therapy for CGD and our studies of gene therapy in the CGD mouse confirm the safety and feasibility of this approach.